Colorectal cancer is the second leading cause of cancer death in the United States, and colorectal adenomas are well-established precursors to these cancers. Without preventive actions, approximately 6% of Americans will develop this malignancy during their lifetime. We propose to examine 3 inter-related pathogenic pathways for colorectal carcinogenesis: the vitamin D axis, inflammation, and insulin/insulin-like growth factor signaling. We will also assess the influence of DNA methylation aberrations on growth factor signaling. Many of the proposed modifiable factors for colorectal neoplasia (low intakes of Vitamins D, calcium and folate, and high intakes of alcohol, obesity, inactivity, and non-use of aspirin) may operate through these pathways. We will examine prospectively and extensively how these modifiable factors may influence colorectal neoplasia risk operating through these pathways. We will utilize data from the Health Professionals Follow-up Study (HPFS) and Nurses'Health Study (NHS), two large ongoing prospective studies of men and women, respectively. Participants for the analysis of cancers will be drawn from the HPFS whereas participants for the analysis of adenomas will be drawn from both cohorts. We will study relevant exposures utilizing (1) multiple questionnaires accumulated over 20 years to assess the influence of long-term exposures including diet, (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant to the pathways of interest. These exposures and genetic factors will be examined in relation to various endpoints including (1) colorectal cancer incidence, (2) colorectal adenoma incidence, (3) specific molecular alterations in colorectal cancer (including K-ras mutation, VEGF expression, microvessel density, loss of expression of p21 and p27, and overexpression of phospho-Akt, FASN, and COX-2), and (4) survival from colorectal cancer following a curative resection of colorectal cancer. By better understanding underlying mechanisms, dose-response relations, inter-relations among factors acting in similar pathways, variation in response due to genetic susceptibility, and specificity in associationsto specific tumor markers, we can solidify and refine recommendations aimed at reducing the incidence and mortality from this largely preventable cancer.